Benzamidoimidazolines

ABSTRACT

Imidazolines having hypotensive and/or anti-inflammatory activity are described. They have the formula:   WHEREIN R1 and R2 are the same or different and each is hydrogen, halogen, lower alkyl or lower alkoxy. An imidazoline having hypotensive activity is 2-benzamido-2-imidazoline, an anti-inflammatory imidazoline is 2,4-dichlorobenzamido-2imidazoline. The new imidazolines are prepared from et

United States Patent n 1 Brown et al.

[ 5-] Apr. 3, 1973 [541 BENZAMIDOIMIDAZOLINES [75] Inventors: David Maxwell Brown, Dorking; Eric Alfred Watts, Harlow, both of England [73] Assignee: Beecham Group Limited, Brentford,

Middlesex, England [22] Filed: Nov. 12, 1970 21 Ap 1. No.2 88,978

[30] Foreign Application Priority Data Nov. 18, 1969 Great Britain ..56,27l/69 [52] U.S. Cl. ..260/309,6, 260/552 R, 260/558 S,

' 260/559 T, 260/999 [51] Int..Cl. .L ..C07d 49/34 [58] Field of Search ..260/309.6

[56] References Cited OTHER PUBLICATIONS ltoh et a1. Chem. Abst. Vol. 71, No. 8l489g (1969, Oct. 27, i969) QDLASI Musinu .et al. Chem. Abst. .Vol. 70, No. 55930d (1969).QDLA51 Shibata Rubber Chem. Abst. Vol.67, No. 82717j (1967).QD1.A51'

benzamido-Z-imidazoline, an

Primary Examiner-Natalie Trousof AttorneyJacobs & Jacobs [57] ABSTRACT lmidazolines having hypotensive and/or anti-inflammatory activity are described. They have the formula:

R1 N-CHz CONHC I R; N-CHz I 2 Claims, No Drawings BENZAMIDOIMIDAZOLINES v This invention relates to novel imidazoline's which have hypotensive and/or anti-inflammatory activity;

The present inventionprovides an imidazoline of formula (l) hydrogen, halogen, lower alkyl or lower alkoxy. In the present specification the terms lower alkyl" and lower alkoxy refer to alkyl and alkoxy groups be chloro-,

-CON=(f-SCH3 v R: NH: (II) with ethylenediamine.

Compounds of formula (11) may be prepared by reacting an acid chloride (Ill) -c0,ci.

with either (a) ammonium'thiocyanatefollowedby ammonia or (b) thiourea, thereby forming a benzoylthiourea (IV) v I R: (IV) methylating agent. In formulas (11) a (W) R, and R,

have the same significance as in formula '(1').

When the methyla ting agent employed is a methyl halidesuch as methyl iodide, the halide salt e.g. iodide, of compounds (11) is formed directly.

One preferred compound of this invention which .on testing in small animals has shown significant hypotensive activity is 2-benzamido-2-imidazoline. One preferred compound which on testing in small animals has shown significant anti-inflammatory activity is 2,4- dichlorobenzamido-2-imidazoline.

The present invention also provides a pharmaceutical composition comprisinga compound of formula (1) together with conventional liquid or solid pharmaceutical carriers or excipients. The compounds and compositions of this invention'can be administered either orally or parenterally.

The following Examples describe the preparation of I some specific compounds of this invention.

EXAMPLE -1 Benzoyl chloride (28.10 g.) wasaddeddropwise to a suspension of ammonium thiocyanate (15.20 g.) in acetone (1.00 ml) at room temperature. The reaction wherein R and R are the same or different and each is mixture was warmed on a water bath for-5 minutes. Excess 5N ammonium hydroxide solution (500 ml.) was added in one portion and the mixture was heated under reflux for 5 minutes. The resulting solution was poured into distilled water (2 L) to giveN-benzoylthiourea .(26.67 g.; 75 percent) as colorless microcrystals, m.p.

N-Benzoylthiourea (18.00 g.) was dissolved in the minimum volume of acetone, treated with excess methyl iodide, and allowed to stand at'room temperature overnight. The resulting colorless crystalline. precipitate of N benzoyl-S-methylpseudothiouronium 'iodide (31.00 g.; 97 percent) m.p. 185C. was filtered and washed with cold acetone. (Found: C, 33.97;'H,

3.48; N 8.68; S,- 9.77 percent; C H IN,OS requires: C, 33.55;H,3.4l;N,8.70;S,9.94 percent).

N-Benzoyl S-methy1pseudothiouronium iodide (1.04 g.) methanol ml.) was added to anhydrous ethylenediamin e.(0.20 g.)'in methanol (5 ml.) and the mixture wa'sallowed .to stand at room temperature.

After 7 days the resulting colorless needles of 2- '-benzamido-2'-imidazoline (0.48 g.; 78 percent) m.p.

(III) Q j-chlorobenzoylthiourea (6.74 g.; 31 percent) m.p. 164

' 165C. (Found: C,,44. 80; H, 3.24;-N, 13.10; S, 14.95;

I and then reacting said benzoylthiourea (IV) with a 184" 7 187C were filtered and washed with methanol (10 ml.). (Found: C, 63.29; H, 5.92;'N, 22.24 percent;

c,,,H,,No requires: c, 63.50; H, 5.82; N, 22.20 percent)..

I EXAMPLE 2 o-Chlorobenzoyl chloride (17.50 g.) and thiourea (7.60 g.) were dissolved in toluene ml.) and heated underreflux for 18hours with-vigorous stirring. After cooling the resulting precipitate was filtered and recrystallized from toluene to give v N-o- Cl,16.53 percent; C H-,ClN,OS requires: C, 44.75; H,

' 3.26;N, 13.25; S, 14.80, Cl, 16.32 percent).

N-o-Chlorobenzoylthiourea (4.80 g. was dissolved in the minimum volume of acetone, treated with excess methyl iodide, and allowed to stand at room tempera- .tureovernight. The resulting colorless crystalline precipitate of N-ochlorobenzoyl-S methylpseuidothiouroniumiodide (6.67 g.'; 84 percent) m.p.,l79 C was filtered and. 'washed with coldacetone (Foundzf C 30.27; H, 2.80; N, 7.73; S, 8.87 percent:

614111060 1163 requires: c, 30.30; H, 2.82 N, 7.85; s.

8.98 percent).

N o-Chlorobenzoyl-S-methylpseudothiouronium iodide (6.67 g.) was dissolved in the minimum of methanol, and the solution was added to anhydrous ethylenediamine (0.94 g.) in methanol (12 ml.). The reaction mixture was allowed to stand at room temperature for 3 days. The resulting precipitate was filtered and recrystallizedv from water to give-2 ochlorobenzamido-2-imidazoline (1.94 g.; 24%) as colorless micro-crystals m.p. 228 229C.

(Found: C, 53.43; H, 4.59; N, 18.59;.Cl, 15.93 percent; 'c,,H,,,c|N,o requires: c, 53.75; H, 4.48; N,

o-Toluoyl chloride (10.00g.) and thiourea(4.92 g.) were dissolved in toluene,( 1.00 ml.) and heated under reflux for. 18 hours with vigorous stirring. After cooling the resultingprecipitant was filtered andrecrystallized from toluene to give N-o-toluoylthiourea (5.00 g.; 41 percent) as colorless microcrystals m.p. 185C (Found: C, 55.43; H, 5.15; N, 14.39; S, 16.41 percent; C H N OS requires C, 55.62; H, 5.16; N, 14.44, S, 16.50 percent).

N-o-Toluoylthiourea (1.94 g.) was dissolved in the minimum volume of acetone treated with excess methyl iodide, and allowed to stand at room temperature'overnight. The resulting colorless precipitant of S- methyl-N-o-toluoylpseudothiouronium iodide (2.24 g.; 66 percent m.p. 157 158C was filtered and washed with cold acetone (Found: C, 35.54; H, 3.86; N, 8.10; S, 9.67 percent; C H IN OS requires: C, 35.70; H, 3.86; N, 8.34; S, 9.52 percent).

S-Methyl-N-o-toluoylpseudothiouronium iodide (7.58 g.) in methanol (20 ml.) was added to anhydrous ethylenediamine (1.35 g) in methanol ml.). The resulting solution was heated under reflux for 1 hour and was then allowed to cool and stand at room temperature for 3 days. The resulting crystalline precipitate was filtered and recrystallized from aqueous g.). The reaction mixture was warmed on a water bath for 5 minutes. Excess 5N ammonium hydroxide (7 ml.) was added dropwise and the mixture was heated under reflux for a further 5 minutes. The reaction mixture was then poured into distilled water (600 ml.). The result ing crystalline precipitate was filtered, dried in vacuo and recrystallized from toluene to give N-(2-6- dimethoxybenzoyl)thiourea (1.84 g.; 31 percent) as pale yellow microcrystals m.p. 236 238C (Found: C, 50.10; H, 5.03; N, 11.49; S,13.58 percent; C H N O S requires: C, 50.00; H, 5.00; N, 11.68; S, 13.32 permethanol to give 2-o-toluamido-2-imidazoline (1.41 g.;

35 percent as colorless microcrystals m.p. 158 159C (Found: C, 65.02; H, 6.42; N, 20.04 percent; C H N 0 requires: C, 65.00; H, 6.40; N, 20.68 percent).

EXAMPLE 4 p-Anisoyl chloride (17.05 g.) was added dropwise to a suspension of ammonium thiocyanate (7.60 g.) in acetone (50 ml.) at room temperature. The reaction mixture was warmed on a water bath for 5 minutes.

Excess 5N ammonium hydroxide solution (90 ml.) was added in one portion and the mixture was heated under reflux for 5 minutes. The resulting solution was poured into distilled water (1L) to give N-panisoylthiourea (16.24 g.; 77 percent) as colorless microcrystals m.p. 210 212C (Found: C, 51.44; H, 4.81; N, 13.24; S, 14.08 percent; C H N O S requires: C, 51.12; H, 5.21;N, 13.27;S, 15.16 percent).

N-pAnisoylthiourea (8.00 ,g.) was dissolved in the minimum volume of acetone, treated with excess methyl iodide and allowed to stand at room temperature overnight. The resulting precipitant was filtered and washed with cold acetone to give N-p-anisoyl-S- methylpseudothiouronium iodide (9.02 g., 68 percent) as colorless microcrystals m.p. 174 178C. (Found: C, 34.40; H, 3.76; N, 7.84; S, 9.10; l, 36.04 percent; CruHmlNzOgS requires C. 34.50; H. 3.70; N, 7.95; S, 9.09; I, 36.08 percent).

A suspension of N-p-anisoyl-S-methylpseudothiouronium iodide (9.09 g.) in methanol (50 ml.) was added to anhydrous ethylenediamine (1.54 g.) in methanol (10 ml.) and the resulting clear solution allowed to stand at room temperature for 3 days. Addition of water (100 ml.) yielded a colorless precipitate which was filtered and recrystallized from water to give 2-p-anisamido-Z-imidazoline (0.93 g.; 17%) as paleyellow microcrystals m.p. 172 174C (Found: C, 60.28; H, 6.03; N, 19.25 percent; C,,H,,N,0, requires: C, 60.25; H,5.93; N, 19.18 percent.

EXAMPLE 5 2-5-Dimethoxybenzoyl chloride (4.75 g.) was dissolved in a minimum amount of acetone and added dropwise to a solution of ammonium thiocyanate (1.81

N-(2.6-Dimethoxybenzoyl)thiourea (3.57 ,g.) was dissolved in a minimum of dry acetone (350 ml.) and treated with excess methyl iodide (4.35 g.). The reaction mixture was allowed to stand at room temperature for 18 hours and then heated under reflux for half an hour. The resulting crystalline precipitate was filtered and dried in vacuo. Further crops were obtained by evaporation of the mother liquors. The combined precipitates were recrystallized from ethanol ether to yield N-(2-6-dimethoxybenzoyl-S-methylpseudothiouronium iodide) (3.72 g.; 65 percent as colorless microcrystals m.p. 178-182C (Found: C, 34.65; H, 3.98; N, 7.25; S, 8.39; l, 33.37 percent; C,,H, 1N O S requires, C, 34.60; H, 3.93; N, 7.35; S, 8.40; I, 33.80 percent).

N-(2-6-Dimethoxybenzoyl-S-methylpseudothiouronium iodide (4.36 g.) in methanol (30 ml.) was added dropwise at room temperature to anhydrous ethylenediamine (0.69 g.) in methanol (20 ml.) and allowed to stand at room temperature for 7 days. The resulting precipitate was filtered, washed with water (30 ml.) and dried in vacuo to yield 2-6-dimethoxybenzamido-2-imidazoline (1.45 g.; 51 percent) as colorless microcrystals m.p. 264C (Found: C, 57.34; H, 6.05; N, 16.78 percent; C H N D requires C, 57.85; H, 6.03; N, 16.86 percent).

EXAMPLE 6 N-(2-4-dichlorobenzoyl)thiourea (5.00 g.) was dissolved in a minimum amount of acetone and treated with excess methyl iodide (5.0 g.). The reaction mixture was heated under reflux for 1 hour on a water bath, treated with an equal volume of dry ether and allowed to cool. The resulting precipitate was filtered, washed with dry ,ether and dried in vacuo to give N- (2,4-dichlorobenzoyl)-S-methylpseudothiouroniurn iodide (6.38 g.; percent) as colorless microcrystals m.p. 139C (Found: C, 27.72; H, 2.21; N, 7.16; S, 8.20 percent; C H,Cl IN,OS requires C, 27.60; H, 2.30; N, 7.15;S,8.18 percent).

N-(2,4-Dichlorobenzoyl)-S-methylpseudothiouronium iodide (20.00 g.) in methanol (45 ml.) was added to anhydrous ethylenediamine (3.10 g.) in methanol (20 ml.). The reaction mixture was allowed to stand at room temperature for 4 days. The resulting precipitate was filtered, washed with methanol and water and dried in vacuo to give 2,4-dichlorobenzamido-2-imidazoline (8.67 g.; 66 229 231C (Found: C, 46.58; H, 3.44; N, 16.36; Cl, 27.45 percent; C H Cl N O requires C, 46.42; H, 3.49; N, 16.26; Cl, 27.52 percent).

EXAMPLE 7 2-6-Dichlorobenzoyl chloride (5.0 g.) and thiourea (1.81 g.) were dissolved in toluene (100 ml.) and heated under reflux with stirring for 48 hours. The hot solution was filtered and allowed to cool. The resulting precipitate was filtered, washed with toluene and dried in vacuo to give N-(2,6-dichlorobenzoyl)thiourea (2.56 g.; 43 percent) as paleyellow microcrystals m.p. 220 222C (Found: C, 38.60; H, 2.36;, N, 11.09; S,

12.89 percent; C H Cl N OS requires C, 38.70; H.

2.41; N, 11.25; S, 12.85 percent).

N-(2,6-dichloroben-zoyl)thiourea (2.83 g.) was dissolved in dry acetone (25 ml.) and treated with excess methyl iodide (10.0 g.). The resulting solution was percent) as colorless microcrystals m.p.

heated under reflux for 2 hours. Thereaction mixture was then concentrated in vacuo to about 5 ml. and treated with dry ether. The supernatant liquors were decanted from the resulting gum, which was dissolved in methanol (30 ml.). This methanolic solution of crude N-(2,6-dichlorobenzoyl)-S-methylpseudothiouronium iodide was added dropwise to a solution of ethylenediamine(0.69 g.) in methanol (5 ml.) at room temperature. The resulting crystalline precipitate (2.08 g was filtered, washed with a little methanol and dried in vacuo. Recrystallization from dimethyl' sulphoxide/water followed by filtration through a column of silica gel G with chloroform as eluent and finally recrystallization from dimethyl sulphox'ide/water gave 

2. 2,4-dichlorobenzamido-2-imidazoline. 